The protein involucrin is a precursor of the cross-linked envelope that forms late in the terminal differentiation of the epidermal keratinocyte. This envelope is the most resistant structure in the skin and is the ultimate barrier between the body and the external environment. Involucrin possesses properties which fit it for its highly unusual function. These properties will be studied in detail--the size and shape of the molecule, its amino acid sequence (from the protein itself and from cloned cDNA), and its interactions with itself and with membrane proteins. As the cell undergoes terminal differentiation, involucrin mRNA appears in the cytoplasm and is translated. The control of mRNA for involucrin will be studied in detail. The basis for the onset of involucrin mRNA accumulation will be examined using cDNA clones presently available, and genomic clones to be prepared. Study of the structure and state of the involucrin gene will be undertaken on cells at different stages of terminal differentiation so as to elucidate the mechanism of gene activation. These studies at the cellular and molecular levels are expected to shed light on the mechanism of differentiation in general, as well as on the particular form exhibited by the epidermal cell. An understanding of the peculiar structure of involucrin, its synthesis, and the details of the cross-linking reaction are fundamental to analysis of disorders of the epidermis. (M)